Expanded genetic carrier screening decreases the risk of conceiving an affected child in both selected and unselected populations

 

Fragestellung:

Does expanded carrier screening (ECS) reduce the risk of conceiving an affected child through assisted reproduction with either own or donated gametes?

Methodik:

Retrospective consecutive cohort study including 2380 women (both patients and donors) and 986 men between March and December 2015. All were tested with CarrierMap (Recombine), an expanded carrier screening test covering 2647 mutation in 311 genes implicated in 311 diseases. DNA samples were prepared and purified following the QIAamp DNA Purification Protocol via QIAcube (QIAGEN). Samples were assayed using the Infinium iSelect HD Custom Genotyping BeadChip platform (Illumina). Donor candidates with a family history of FXS or more than 45 CGG triplets repetitions, mental retardation, chromosomal abnormalities, genetics or neurological conditions are excluded from the donor program. In addition 894 matches to identify the reproductive risk were performed.

Ergebnisse:

A total of 3366 expanded carrier screening test were performed, 2380 women and 986 men. Of the 3366 individuals tested, 1458 (43.3%) were positive for at least one mutation; of them, 1091 (32.4%) carried one mutation, 306 (9.1%) two and 54 (1.6%) three; 7 individuals carried four or more of the mutations analyzed. The most frequent mutations found were for Nonsyndromic Hearing Loss and Deafness (GJB2 Related): 152 (10.4%); carrier frequency 1: 22. Pseudocholinesterase Deficiency: 98 (6.7%); 1: 34. Fragile X syndrome: 97 (6.6%); 1: 34. Cystic Fibrosis: 89 (6.1%), 1: 38. Familial Mediterranean fever (FMF): 82 (5.6%), 1: 41. Alpha-1-Antitrypsin Deficiency: 74 (5.0%), 1: 45. 21-Hydroxylase-Deficient-Nonclassical Congenital Adrenal Hyperplasia: 40 (2.7%), 1: 84. Sickle-Cell Anemia: 29 (1.9%), 1: 116. Out of the total of 894 matches (747 between donor and patient, 114 between two donors and 33 between patients), 26 (2.9%) showed a high reproductive risk, since both members were carrier for mutations leading to the same disease, thus having a 1 in 4 probability to generate an effected child. While matching with high reproductive risk involving donor gametes were replaced with different donors, the 2 couples of patients with high reproductive risk received genetic counseling and PGD was recommended.

Schlussfolgerung:

Expanded carrier screening effectively detects couples at a higher risk of conceiving an affected child with a positive match rate of 2.9%. This value should be higher in unselected patients, as most attempted matchings were made with donors preselected for lower carrier status by extensive family history review and initial specific genetic testing.